1. Field of the Invention
The present invention relates generally to prevention or treatment of Alzheimer's disease or related neurological pathologies; particularly, it relates to the use of β-adrenergic or opioid receptor antagonists for treating Alzheimer's diseases.
2. Background Art
Alzheimer's Disease (AD), which is characterized by progressive dementia and personality dysfunction, is the most common neurodegenerative disorder associated with aging. AD affects 5-11% of the population over the accumulation of amyloid plaques in the vicinity of degenerating neurons and reactive astrocytes. D. J. Selkoe, Annu. Rev. Neurosci. 17, 489 (1994).
Amyloid plaque, composed mostly of amyloid β (Aβ), is a hallmark of AD neuropathology, and formation of amyloid plaques is considered a primary cause of AD. In addition, recent studies have revealed that the diffusible oligomeric Aβ may also be neurotoxic and potentially AD-related. Walsh, D. M. et al., “Naturally Secreted Oligomers of Amyloid Beta Protein Potently Inhibit Hippocampal Long-Term Potentiation in vivo,” Nature 416, 535-9 (2002)
Aβ is generated from β-amyloid precursor protein (APP) via sequential cleavages by β- and γ-secretases. As illustrated in FIG. 1, APP is cleaved by β-secretase to produce a soluble APPs-β fragment and a C99 fragment, the latter is in turn cleaved by γ-secretase to produce the Aβ fragment and a C60 fragment.
The amyloid fragments (Aβ) comprise at least two forms, a 40 amino acid form (Aβ40) and a 42 amino acid form (Aβ42). The 42 amino acid form (Aβ42) is more prone to plague formation and is considered more relevant to AD etiology. γ-Secretase plays a pivotal role in AD because it determines the ratio of the two main Aβ species (Aβ40 and Aβ42).
As shown in FIG. 2, γ-secretase complex includes at least four essential components: presenilin (PS), nicastrin (NCSTN), APH-1, and PEN-2. Mutations in the putative catalytic component presenilin-1 (PS1) account for most cases of familial AD (FAD), suggesting that γ-secretase may be critically involved in the pathogenesis of AD (at least the pathogenesis of FAD).
Although the correlation between presenilin-1 mutations and FAD provides a clue to genetic cause of AD, FAD accounts for less than 10% of all AD cases. In contrast, most AD cases are sporadic in nature, indicating that factors other than presenilin-1 mutations are more important in the pathogenesis of AD. Therefore, it is important to investigate how other factors or environmental influences contribute to AD pathogenesis.
Previous studies have shown that Aβ production in cell cultures can be reduced by activation of intracellular signaling pathways or membrane receptors such as muscarinic acetylcholine receptors. Recent evidence also shows that Aβ levels and amyloid plaque formation can be influenced by somatostatin or environmental factors.
APP processing is also regulated by neurotransmitters and synaptic activity. For example, activation of neurotransmitter receptors, which are coupled to phosphotidylinositol (PI) hydrolysis or to protein kinase C (PKC) activation, can promote APP metabolism and decrease amyloid formation. (Ulus and Wurtman, J. Pharm. Exp. Ther., 281, 149 (1997)) On the other hand, activation of neurotransmitters coupled to cAMP production can suppresses both constitutive and PKC/PI-stimulated APPs secretion in astroglioma cells and in primary astrocytes. (Lee et al., J. Neurochem., 68, 1830 (1997)) The inhibitory effect of cAMP on APPs secretion may be specific for astrocytic cells because cAMP and PKA activation reportedly stimulate APPs secretion in pheocbromocytoma PC-12 and human embryonic kidney cells. (Xu et al., PNAS USA, 93, 4081 (1996); Marambaud et al., J. Neurochem., 67, 2616 (1996)) In any event, the above results indicate that changes in neurotransmitter levels or second messenger signaling, which may result from neuron degeneration and synapse loss in AD, can disrupt APP processing and lead to accumulation of amyloidogenic or neurotoxic APP fragments.
Furthermore, it has been shown that modulation of β-adrenergic receptors, which leads to elevated cAMP, can increase the synthesis of APP in astrocites. Based on this finding, U.S. Pat. Nos. 6,187,756 and 6,043,224, issued to Lee et al., discloses methods for alleviating neurological disorders stemming from the aberrant expression of APP by using β-adrenergic receptor antagonists that modulate the cAMP levels. In this approach, β-adrenergic receptor antagonists are used to suppress the synthesis of APP, through modulation of cAMP levels.
In addition to suppression of APP synthesis, modulation of APP metabolism may also be used to alleviate neurological disorders associated with APP-related plaque formation. For example, U.S. Pat. No. 5,385,915, issued to Buxbaum et al., discloses methods and compositions for affecting APP processing using agents that regulate protein phosphorylation, i.e., agents that affect kinases or phosphatases. The modulation of APP processing in turn leads to the regulation of the production of Aβ peptides that accumulates in amyloidogenic plaques.
Similarly, in U.S. Pat. No. 5,242,932, Gandy et al. disclose and claim a method of modulating or affecting the intracellular trafficking and processing of proteins (including APP) in mammalian cells, using chemicals such as chloroquine and primaquine.
While these prior art methods seem to be effective in modulating the production and metabolism of APP, and hence the formation of plaques, there remains a need for more methods and reagents for the treatment and prevention of AD.